Replication stress is a common feature of cancer cells. Ataxia telangiectasia‐mutated (ATM) and Rad3‐related (ATR) signalling, a DNA damage repair (DDR) pathway, is activated by regions of single‐stranded DNA (ssDNA) that can arise during replication stress. ATR delays cell cycle progression and prevents DNA replication fork collapse, which prohibits cell death and promotes proliferation. Several ATR inhibitors have been developed in order to restrain this protective mechanism in tumours. It is known, however, that despite other effective anticancer chemotherapy treatments targeting DDR pathways, resistance occurs. This begets the need to identify combination treatments to overcome resistance and prevent tumour cell growth. We conducted a drug screen to identify potential synergistic combination treatments by screening an ATR inhibitor (VE822) together with compounds from a bioactive small molecule library. The screen identified adefovir dipivoxil, a reverse transcriptase inhibitor and nucleoside analogue, as a compound that has increased cytotoxicity in the presence of ATR, but not ATM or DNA‐dependant protein kinase (DNA‐PK) inhibition. Here we demonstrate that adefovir dipivoxil induces DNA replication stress, activates ATR signalling and stalls cells in S phase. This simultaneous induction of replication stress and inhibition of ATR signalling lead to a marked increase in pan‐nuclear γH2AX‐positive cells, ssDNA accumulation and cell death, indicative of replication catastrophe.

中文翻译：

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阿德福韦酯可引起DNA复制压​​力并增强ATR抑制剂相关的细胞毒性。

复制压力是癌细胞的共同特征。共济失调毛细血管扩张突变（ATM）和Rad3相关（ATR）信号，一种DNA损伤修复（DDR）途径，被复制压力下可能产生的单链DNA（ssDNA）区域激活。ATR延迟细胞周期进程并防止DNA复制叉崩溃，从而阻止细胞死亡并促进增殖。为了抑制肿瘤的这种保护机制，已经开发了几种ATR抑制剂。然而，已知尽管有其他针对DDR途径的有效抗癌化学疗法，但仍会产生耐药性。这就需要确定联合疗法来克服耐药性并防止肿瘤细胞生长。我们进行了药物筛选，通过筛选ATR抑制剂（VE822）以及具有生物活性的小分子文库中的化合物来确定潜在的协同组合治疗。该筛查确定阿德福韦酯（逆转录酶抑制剂和核苷类似物）是在存在ATR的情况下具有增加的细胞毒性的化合物，而不是对ATM或DNA依赖性蛋白激酶（DNA-PK）抑制的化合物。在这里，我们证明阿德福韦酯可诱导DNA复制应激，激活ATR信号并使细胞停滞在S期。复制压力的同时诱导和ATR信号的抑制导致泛核γH2AX阳性细胞，ssDNA积累和细胞死亡显着增加，这表明复制灾难。该筛查确定阿德福韦酯（逆转录酶抑制剂和核苷类似物）是在存在ATR的情况下具有增加的细胞毒性的化合物，而不是对ATM或DNA依赖性蛋白激酶（DNA-PK）抑制的化合物。在这里，我们证明阿德福韦酯可诱导DNA复制应激，激活ATR信号并使细胞停滞在S期。复制压力的同时诱导和ATR信号的抑制导致泛核γH2AX阳性细胞，ssDNA积累和细胞死亡显着增加，这表明复制灾难。该筛查确定阿德福韦酯（逆转录酶抑制剂和核苷类似物）是在存在ATR的情况下具有增加的细胞毒性的化合物，而不是对ATM或DNA依赖性蛋白激酶（DNA-PK）抑制的化合物。在这里，我们证明阿德福韦酯可诱导DNA复制应激，激活ATR信号并使细胞停滞在S期。复制压力的同时诱导和ATR信号的抑制导致泛核γH2AX阳性细胞，ssDNA积累和细胞死亡显着增加，这表明复制灾难。在这里，我们证明阿德福韦酯可诱导DNA复制应激，激活ATR信号并使细胞停滞在S期。复制压力的这种同时诱导和ATR信号的抑制导致泛核γH2AX阳性细胞，ssDNA积累和细胞死亡显着增加，表明复制灾难。在这里，我们证明阿德福韦酯可诱导DNA复制应激，激活ATR信号并使细胞停滞在S期。复制压力的同时诱导和ATR信号的抑制导致泛核γH2AX阳性细胞，ssDNA积累和细胞死亡显着增加，这表明复制灾难。